The skin and soft tissue infections in hematological patients

Purpose of review Skin and soft tissue infections (SSTIs) in patients with hematological malignancies are frequent, but dedicated epidemiological studies are limited. The aim of this review is to provide updated description of the main etiological agents, differential diagnosis, and treatment. Recent findings In addition to common causes of bacterial skin infections in any kind of patients, such as streptococci and staphylococci (the letter frequently resistant to methicillin), Pseudomonas aeruginosa is a frequent agent in patients with hematological malignancies, with high virulence and typical infection presenting as ecthyma gangrenosum. Among fungi, fusariosis is the mold infection most frequently associated with skin lesions, although other molds and yeasts (including Candida tropicalis) should be also considered. External infections associated with central venous catheters are frequent in the hematological setting, and in addition to staphylococci, Gram-negative bacteria, fungi, and even rapid growing nontuberculous mycobacteria should be considered. Immunodeficiency might either blunt the typical inflammatory response and make sign or symptoms less evident, or predispose the patients to rapid progression of skin infection to subcutaneous tissues or dissemination. Summary SSTIs in hematology patients can be caused by various infectious agents resulting in similar clinical presentation. Rapid and accurate diagnosis is fundamental in order to reduce morbidity and mortality.


INTRODUCTION
Skin and soft tissue infections (SSTIs) are frequent but sometimes underestimated complications in the hematological setting, particularly in recipients of hematopoietic stem cell transplant (HSCT). Unlike for other more severe infectious syndromes such as bloodstream infection or pneumonia, there are few systematic descriptions and epidemiological studies of SSTIs in hematology.
Even tough infectious agents are the most frequent cause of skin lesions, other pathologies of noninfectious origin, such as direct invasion of neoplastic cells, paraneoplastic reactions, neutrophilic dermatoses such as Sweet's syndrome and pyoderma gangrenosum, graft-versus-host disease (GvHD), medications (including both traditional chemotherapy and targeted therapies), and allergic reactions should also be considered in the differential diagnosis and constitute important diagnostic challenge [1].
The aim of this review is to provide updated description of the main SSTIs in patients with hematological disorders and to highlight the peculiarity of SSTIs in this setting. Although a separate paper is dedicated to fungal SSTI, those typical for hematology patients will be briefly discussed here. The treatment of all the causes of SSTI developing in hematology patients is beyond the scope of this review.

RISK FACTORS AND PARTICULARITIES OF SKIN AND SOFT TISSUE INFECTIONS IN HEMATOLOGY SETTING
Mucositis, epithelial damage and myelosuppression that follow the underlying disease and/or the chemotherapeutic cytotoxic regimen, predispose to bacterial translocation and infections, usually affecting integumental surfaces such as respiratory tract, gastrointestinal tract and skin [2]. Other risk factors for SSTI in this setting are the quasi-universal and prolonged use of central venous catheters, skin microbiome dysbiosis, and poor wound healing because of immunocompromised state. Finally, patients with hematological malignancies, and especially HSCT recipients, might have other comorbidities further predisposing to SSTI such as diabetes (frequently steroid-induced), renal failure, skin fragility caused by GvHD or malnutrition [3,4].
In addition to localized infections such as erysipelas and cellulitis, which are frequently caused by the same pathogens as in immunocompetent individuals, hematologic patients are prone to disseminated fungal, viral and bacterial infections, with metastatic skin localizations that could lead the diagnostic work-up of an unrecognized pathology [5].
Two main issues should be kept in mind when evaluating skin lesions in an immunocompromised patient with a hematological disorder. First, patients frequently have an atypical clinical presentation, ranging from mild signs and symptoms, because of very limited inflammatory response stemming from an impaired immune system [2], to catastrophic rapidly progressive invasive infections with large areas of tissue necrosis involving the fascia caused by the impossibility of immune system to limit the progression of infection [6 & ,7 & ]. Second, infrequent causes of skin infection, such as Nocardia, rare molds or nontuberculous mycobacteria (NTM) should always be considered, particularly in patients with a deficit of cellular immunity such as those with HSCT or chronic lymphocytic leukemia (CLL). Therefore, specific dedicated diagnostic methods, frequently involving skin biopsy, are warranted. The main diagnostic procedures indicated in case of SSTIs in patients with hemato-logical disorders are outlined in Table 1.

KEY POINTS
Skin and soft tissue infections in the hematological patients are underestimated but frequent complications whose clinical presentation can range from limited inflammatory response to catastrophic rapidly progressive invasive infections, both stemming from an impaired immune system. P. aeruginosa is one of the most important pathogens in this setting and should always be considered when choosing empirical antibiotic therapy.
The profound immune suppression secondary to malignancy and its therapies predisposes to skin infections with pathogns including bacteria, virus, and rare opportunistic pathogens such as Nocardia, rare molds, or nontuberculous mycobacteria.
Skin lesions are frequently the most noticeable if not the first manifestation of disseminated infectious diseases, whose identification can aid in accelerating the diagnosis in order to reduce the associated morbidity and mortality (e.g. in fusariosis).
As therapies and management of hematological malignancies evolve, with the recent introduction of targeted therapies, the experience of the associated infectious complications and their manifestations including skin involvement remains limited.
Prompt and aggressive diagnostic approach is warranted to establish early diagnosis and the optimal treatment.

BACTERIAL SKIN AND SOFT TISSUE INFECTIONS
Erysipelas, cellulitis, and other soft tissue infections are commonly caused by pyogenic bacteria such as Streptococcus spp. and Staphylococcus aureus. Cutaneous manifestations, such as areas of localized inflammation with calor, rubor, tumor, and dolor, are usually accompanied by systemic symptoms such as fever, asthenia, and malaise [5]. Localized sings of inflammation might be missing or attenuated, particularly during neutropenia, but may increase significantly upon neutrophil recovery. Because patients with hematological malignancies are rapidly colonized with nosocomial flora and might undergo important microbiota changes due to previous chemotherapies and antibiotic treatments, resistant bacterial strains should be always taken into account when choosing empirical antibiotic therapy. Immunocompromised patients are at risk of disease progression with dissemination and possible involvement of the subcutaneous structures such as the skeletal muscle or the fascia [8].

Deep subcutaneous infections
Pyomyositis is an acute intramuscular infection at risk for rapid progression with systemic toxicity, usually caused by methicillin-resistant S. aureus (MRSA) and less commonly by streptococci, including Streptococcus pneumoniae, presenting with painful swelling and muscular functional impairment. It has been recently described in the context of CLL treated with imatinib and allogenic HSCT [9,10]. In a comprehensive review of 44 cases of pyomyositis associated with hematological malignancy, death occurred in 11.4% of patients [11].
Necrotizing fasciitis is a rare fulminant infection with a progressive destruction of the skin and subcutaneous structure, which can be polymicrobial (anaerobes and coliform bacteria)or monomicrobial (Streptococcus pyogenes or Clostridia sp. ]. Common clinical symptoms and signs include persistent fever, erythema, and swelling with or without fluctuation and fistula in the perianal region. As with other bacterial infections, local signs may be blunted in neutropenic patients, who usually present only with fever and perirectal pain [15]. Coliform and enteric pathogens are the most frequent organisms recovered from blood cultures or local drainage, followed by P. aeruginosa and Enterococcus spp. Mortality rate, even with antibiotic treatment and surgical debridement, can reach 2.4% [14

Ecthyma gangrenosum
Pseudomonas aeruginosa is an important pathogen in neutropenic patients, causing 5-10% of bloodstream infections [17]. Ecthyma gangrenosum is a form of necrotizing vasculitis usually caused by P. aeruginosa. This peculiar syndrome, typical of the hematological setting, is associated with high mortality and early recognition is crucial for guiding antibiotic treatment. The skin lesion(s) commonly presents as an erythema surrounded-nodule eventually evolving to a necrotic ulcer with a central black eschar (Fig. 1 ]. Ecthyma gangrenosum can appear anywhere in the body but most commonly affects the anogenital and axillary areas, followed by the extremities, trunk and face. In individuals with the bacteremic form of ecthyma gangrenosum, the source of infection and other localization (CVC or pneumonia) must be carefully looked for. Targeted antibiotic therapy may be sufficient, although surgical excision of necrotic lesions or abscesses might be necessary [22 & ].

Nocardia
Nocardia, an environmental Gram-positive pathogen, causes a rare but severe infection in immunocompromised patients. Most cases of nocardiosis in The SSTIs in hematological patients Ungaro and Mikulska the hematologic setting occur after allogeneic HSCT with an incidence rate between 0.3% and 1.7% and a mortality rate that could exceed 50% in disseminated disease [23,24]. Notably, low dose of trimethoprim/sulphametoxazole used for pneumocystosis and toxoplasmosis prophylaxis seems to be inadequate in preventing posttransplant nocardiosis [23,25 & ]. During disseminated disease, metastatization from lungs to skin and other organs such as brain is frequent. In patients with T-cell suppressed function such as those who underwent HSCT, solid organ transplantation, or high-dose corticosteroid therapy, secondary skin lesions during disseminated disease have been described to occur with a rate between

Nontuberculous mycobacteria
Nontuberculous mycobacteria (NTM) infections are increasingly detected in immunocompromised patients, especially in those with a cell-mediated immune deficiency. Availability of improved molecular diagnostic methods, widespread use of immunosuppressive therapies, including HSCT, and improved survival of patients with hematological malignancies have all led to an increase in the incidence of NTM [ Skin is commonly involved during NTM disease, either after direct environmental inoculation of the pathogen at the site of trauma or following disseminated infections with hematogenous metastatic spreading to the skin. NTM predilect the skin of distal cooler areas such as joint surfaces and extremities [37]. The lesions appear usually as multiple erythematous violaceous nodules, usually painful, with a subacute progression to necrosis and suppuration, with local lymphadenopathy. Skin biopsy is mandatory for a correct diagnosis, with histopathology showing suppurative inflammation with limited granuloma formation and acid fast bacilli [30].
Infections of CVC with rapidly growing NTM, including outbreaks in hematology patients caused by water contamination, have been reported [40,41].
The management of NTM infections has already been reviewed elsewhere [42,43 &

VIRUSES
Reactivation of latent infections is the most common cause of viral skin infections in hematology, particularly in patients with prolonged T-cellmediated immunosuppression.
Herpes viruses, such as varicella zoster virus and herpes simplex virus, are the most frequently involved, although the incidence of these infections was significantly reduced with common use of acyclovir or valacyclovir prophylaxis in seropositive patients with acute leukemia, certain chronic lymphoproliferative malignancies such CLL or bortezomib-treated patients with multiple myeloma, and after HSCT [45,46 & ]. If present, VZV reactivation may often result in disseminated shingles, particularly if not promptly recognized and treated, whereas hemorrhagic lesions may be present in thrombocytopenic patients. In HSCT recipients, particularly during preengraftment phase, maculopapular diffuse rash can be caused by reactivation of HHV-6, and differential diagnosis usually include allergic rash, mainly to medications used, and immune-mediated process, such as engraftment syndrome or GvHD [1,47,48]. Kaposi sarcoma is a rare but well recognized HHV-8-mediated cause of neoplastic skin lesions [49 & ]. Cutaneous lesions usually present as multiple, pigmented, raised or flat, asymptomatic papules or nodules, which vary in color from pale pink to vivid purple and may evolve into larger plaques. Occasionally, lesions may present as exophytic, painful ulcerated and bleeding nodules. In the most recent literature review of Kaposi sarcoma after HSCT covering the 1987 -2018 period, Cesaro et al. described an incidence 0.17% in allogeneic and 0.05% in autologous HSCT.
The organ most commonly affected was skin (9/13 cases) with purple to violaceus cutaneous nodules, followed by oral mucosa (4/11) and visceral involvement (3/11)   ]. The outcome of this rare but serious infection is usually poor, with a survival rate of 43% at 90-days described in a review of 233 cases [63], probably because of the presence of disseminated disease and a high fungal burden when the first clinical manifestations appear [60 && ]. Nevertheless, the increased use of voriconazole and of combination therapies has led to a 21% increase in survival rate in the last decade [63].
Despite being the most frequent mold causing IFIs in hematology, Aspergillus spp. is an uncommon cause of skin lesions which occur in 1-5% of invasive infections [60 && ,64]. The most recent literature review that focused on cutaneous manifestations of invasive aspergillosis found metastatic skin lesions being erythematous and disseminated papules or nodules with a scarce propensity to secondary necrosis, in contrast to other molds such as Mucorales [64].
Finally, in case of mucormycosis, skin infection is the third most common presentation after rhinocerebral and pulmonary syndromes [65 & ]. It is usually seen in patients with hematologic malignancies, in particular AML, and has been recently described in a patient undergoing ibrutinib therapy for CLL [66 & ]. The onset of skin infection is acute, usually during the course of a rhinocerebral or disseminated infection. The infection is usually localized, featuring a necrotic eschar surrounded by erythema involving palate or nasal mucosa and/or zygomatic or orbital region [67]. Disseminated skin lesions are less common, they may involving the extremities, the trunk and possibly the head, and are burdened with a very high mortality rate (50-94%) [ ]. A recent comprehensive literature review found 100 cases of Candida skin lesions occurring in neutropenic patients with disseminated candidiasis and reported that they occur more commonly in the setting of induction therapy for de novo or relapsed acute leukemia (86% of cases) and were mainly maculopapular erythematous lesions disseminated through the trunk and extremities [69 && ]. The species most commonly implicated were C. tropicalis (68%) and C. krusei (15%), followed by C. albicans (10%). Particularly, disseminated maculopapular lesions during C. tropicalis infection occurred in 40% of neutropenic patients without fluconazole prophylaxis, while papules and nodules were less common during C. krusei disseminated infection in patients receiving fluconazole prophylaxis. Mortality rate associated with these manifestations during candidemia was high (45.4%) [69 && ]. Among the included studies, only five mainly old studies reported the incidence of skin lesions during candidemia in neutropenia and it was in median 35.8%, ranging from 11.5 to 44% [69 && ]. Finally, Cryptococcus neoformans is an uncommon pathogen in the hematologic patients, possibly because of widespread use of fluconazole prophylaxis, affecting those with severe numeral or functional lymphopenia such as in course of CLL. Skin manifestations are not common, compared to lung or meningeal involvement, with multiple skin-colored to pink round papules with an erythematous rim similar to molluscum contagiosum [70 & ].  [71 & ]. According to guideline definitions, local infections of CVCs include localized entrance or exit-site infections (with erythema and local discharge), infections of the tunneled tract (with tenderness, induration, and erythema along the subcutaneous tract of the catheter for more than 2 cm) and/or infections of the pocket (with tenderness, induration, and erythema of the pocket; purulent drainage with possible device rupture; erosion of overlying skin) [71 & ,73]. Pathogens most commonly responsible of CVCs-related infections (recovered from blood cultures or local swabs [74]) are coagulase-negative staphylococci, S. aureus and Candida, however there has been an increase in infections caused by gram-negative bacteria (in particular P. aeruginosa, K. pneumoniae, E. coli, and Acinetobacter spp.) and rapid-growing mycobacteria [

CONCLUSION
SSTIs in hematology patients can be caused by numerous different infectious agents resulting in similar clinical presentation. Immune system alteration predisposes to infrequent opportunistic infections and to atypical clinical presentation of common syndromes, further complicating the scenario. Rapid and accurate diagnosis is fundamental in order to reduce the morbidity and mortality in this setting.

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Financial support and sponsorship None.
Conflicts of interest M.M. received speaker and board member fees from Pfizer, MSD, Biotest, Gilead and Janssen, all outside the submitted work. R.U. has no conflicts of interest.